1. Field of the Invention
The present invention relates to novel uses of 4,17β-dihydroxyandrost-4-ene-3-one (hereinafter 4-hydroxytestosterone) and its salts and esters, to a process for their preparation, to pharmaceutical compositions containing them, and to the use of said compounds for the prophylaxis and treatment of certain diseases in mammals, in particular cancers.
2. Discussion of the Related Art
After colorectal cancer breast cancer is the most frequent cancer disease in the western world despite the fact that it affects almost exclusively women. In Germany, breast cancer amounts to about 20% of all cancer types diagnosed in women. The therapy in most of the cases consists of surgical removal of the tumour (lumpectomy) or complete removal of the affected breast if the size of the tumor prevents breast conserving therapy. In both cases the operation is followed by drug therapy. A particular complication of breast carcinomas is the high potential of metastatic spread into other organs particularly liver, brain, bones and the skin. Therefore the operation is followed by drug therapy (adjuvant therapy). This therapy is also aimed at preventing local recurrence of the disease.
If the removed tumors were exhibiting estrogen receptors, antiestrogens are used (Tamoxifen or aromatase-inhibitors. The lack of estrogen receptors leads to a postoperative drug therapy using cytostatic drugs.
Tamoxifen binds to the estrogen receptor (ER) and blocks the growth promoting effect of estrogens. Aromatase-inhibitors block the final step in the production of estrogens from androgenic precursors (c-19-steroids). They either bind irreversibly to the active site of the enzyme (aromatase-inactivators, i.e. steroidal aromatase-inhibitors: 4-hydroxyandrostenedione (Formestane=LENTARON®), or Exemestane (AROMASIN®)) or inhibit competitively the cytochrome p 450 part of the enzyme (nonsteroidal aromatase-inhibitors: Anastrozol (ARIMIDEX®) and Letrozol (FEMARA®).
If the breast cancer exhibited an overexpression of the Her2neu gene, antibodies against this cell-surface protein are given intravenously such as e.g. Trastuzumab (HERCEPTIN®).
Basic and clinical data indicate that aromatized metabolites of androgens, i.e. the estrogens, are the hormones involved in the pathogenic cellular changes associated with the growth of some hormone-dependent cancers, such as breast, endometrial and ovarian carcinomas. Aromatase has recently been recognized as an enzyme that is capable to synthesize estradiol directly in tumours.
Endogenous estrogens are ultimately formed from either androstenedione or testosterone as immediate precursors. The local production of estrogens in the breast tissue, especially in the tumour cells itself, had been regarded to be of great importance for the therapy of the disease. In this context, aromatization of the steroidic ring A performed by the enzyme aromatase, and its inhibition had been considered to play a major role in anti breast cancer approaches.
Prior to the present invention, conventional therapeutic approaches to address breast cancer in women—besides other concepts based on estrogen receptor antagonists or therapeutic antibodies—therefore focused on an aromatase-inhibiting action itself. Accordingly, steroidal substances which had been reported to be endowed with an aromatase-inhibiting action have been described, for example Δ1-testololactone [U.S. Pat. No. 2,744,120], 4-hydroxy-androst-4-ene-3,17-dione and esters thereof [see, for example, U.S. Pat. No. 4,235,893], 10-(1,2-propadienyl)-estr-4-ene-3,17-dione (U.S. Pat. No. 4,289,762], 10-(2-propynyl)-estr-4-ene-3,17-dione [J. Amer. Chem. Soc., 103, 3221 (1981) and U.S. Pat. No. 4,322,416], 19-thioandrostene derivatives (Europ. Pat. Appl. 100566), androsta-4,6-diene-3,17-dione, androsta-1,4,6-triene-3,17-dione [G.B. Pat Appl. 2,100,601A] and androsta-1,4-diene-3,17-dione [Cancer Res. (Suppl.) 42,3327 (1982)].
Clinical studies conducted with estrogen-receptor (ER) antagonists and aromatase inhibitors however showed that these compounds were not able to exert a significant and sufficient inhibitory effect on tumour proliferation and/or growth. For example, TAMOXIFEN® based therapy suffers from drawbacks such as tachyphylaxy (therapy failure) and the fact that its effects in some cells are estrogen-like (e.g. risk for thrombosis and edometrial cancer) being the reason that TAMOXIFEN® can not be administered for a period longer than 3 to 5 years. Newer drugs such as aromatase inhibitors can in principle only be used in post-menopausal women and, furthermore, are only effective on ER-positive tumours. Estrogen receptor negative tumors have a worse prognosis and can be postoperatively only treated by cytostatic drugs and in some cases by intravenously given antibodies to the Her2neu antigen. “Hormonal” treatment with selective estrogen receptor modulators (SERMs) such as tamoxifen or raloxifen or aromatase-inhibitors has proven to be ineffective. “Hormonal” treatment is lifelong and usually well tolerated. There is no “hormonal” treatment for ER-negative breast cancers so far.
It could be shown (J. Szelei et al., “Androgen-Induced Inhibition of Proliferation in Human Breast Cancer MCF7 Cells Transfected with Androgen Receptor”, Endocrinol., 138, no. 4, 1406-1412, 1997) that stable transfected cells expressing AR acquire the ability to respond to androgen by evoking an end of cellular proliferation. A more recent report (J. Ortmann et al., “Testosterone and 5α-dihydrotestosterone inhibit in vitro growth of human breast cancer cell lines”, Gynecol. Endocrinol. 2002; 16:113-120) shows that testosterone and 5α-dihydrotestosterone (DHT) can inhibit cell proliferation in certain cell lines. Testosterone itself has a similar effect. It clinical usefulness however is hampered by the fact that it undergoes rapid metabolization to either estradiol or dihydrotestosterone (DHT). The local formation of estradiol from testosterone within the breast cancer by local aromatase activity promotes cancer-growth.
On the other hand, AR itself had been regarded as a modulator of processes involved in differentiation, homeostasis, and development of male secondary characters. Thus, AR-directed treatment schemes had been focused on androgen-related diseases in men, including hypogonadism, male infertility, prostate cancer, delay of puberty, hirsutism, androgen-deficient diseases, androgen replacement in aging men, and male pattern baldness. In this context, a disclosure of U.S. Pat. No. 2,762,818A does not go beyond using 4-hydroxytestosterone and its esters, based on their androgenic and anabolic properties, to treat an androgen deficiency status itself. There was however neither a purpose nor a finding which would suggest an activity on breast cancer cells or on effects from which an efficacy against the disease conditions according to the present invention could have been deduced. Further, US2003/0229063A addresses low androgen to estrogen ratios in men (leading to endocrine disorders) and only for this purpose attempts to make use of 4-hydroxytestosterone based on an asserted aromatase-inhibiting effect alone.
In WO 2005/062760 incorporated herein in its entirety by way of reference, possible roles of androgen receptor (AR) in prostate carcinogenesis and breast cancer is discussed, and methods for breast cancer diagnosis by assaying the presence of AR are presented. However, in terms of therapeutic concepts, WO 2005/062760 is limited to control AR itself, not androgen mediated activity, in the context of mammary gland development by inhibiting AR activity.
For certain indications, the present invention now provides successful other therapeutic approaches involving androgen-receptor (AR) specific compounds that exert testosterone-like effects (in particular anabolic effects) in AR-positive cells and tissues and are not metabolized by aromatase.